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Raman Spectroscopy to Detect Traumatic Brain Injuries: An Interview with Pola Goldberg Oppenheimer

January 10, 2024

In a recent study from the University of Birmingham, a group of researchers led by Pola Goldberg Oppenheimer aimed to develop a better technology for rapid point-of-care diagnostics (PoC) for early-stage traumatic brain injury (TBI) (1). The team used a combination of Raman spectroscopy and fundus imaging of the neuroretina to assess TBIs in patients.

TBIs can affect how the brain works. More than 135 million people globally live with TBIs, and 69,000 TBI-related deaths occurred in the United States in 2021 (2). These can stem from incidents like falls and motor vehicle crashes. However, due to the lack of early symptoms of TBI, there is a need to develop better technology to detect them at earlier stages.

Spectroscopy sat down with Goldberg Oppenheimer to discuss her research and what advancements are needed to detect TBI in patients at earlier stages.

Q: What are the current challenges with detecting TBI early in patients?

A: TBI is a leading cause of morbidity and mortality worldwide, and it is becoming one the major challenges of the 21st century. By 2030, TBI is projected by the WHO to become the third largest cause of neurological disability and death worldwide. In the UK alone, each year, there is approximately 1 head injury admission every 3 minutes. Moreover, 2 million people are living with long-term disabilities, placing a major burden on healthcare providers, and costing billions to society and the economy.

While life-changing decisions must be made rapidly, it is notoriously hard to diagnose at the point-of-care, resulting in incorrect patient management and the chances of an individual suffering cognitive or physical impairment massively increasing. With millions affected annually, the burden that TBI imposes on society makes it a pressing public health and medical problem.

Current diagnostic methods are woefully inadequate, either requiring large equipment, long waiting times, being highly invasive, or not sensitive and timely enough. Point-of-care technology for TBI does not currently exist. There is, therefore, an urgent need for new technologies to achieve timely intervention through rapid and accurate diagnostics at the PoC.

Q: How does this system improve what is currently clinically available?

A: Our portable device will be designed to detect neurotrauma at PoC, (e.g., roadside/ pitch-side/austere combat environment), where no expert evaluation or urgent radiological investigations are immediately available.

PoC technology would reduce mis-triage of injury severity, save healthcare costs (both over- and under-triage are expensive) and improve outcomes by guiding early management. Our spectroscopic technique will be designed for use on-site by doctors and ambulance crews to provide timely and cost-effective diagnosis and triage. Rapid diagnosis in the early clinical phase in a non-invasive, cost-effective way will allow the platform a range of improvements in personalized medicine and management. It would improve triage and diagnosis, reducing the strain on the healthcare system. TBI has a high complication rate, creates prolonged post-concussion symptoms and post-traumatic neuro-disorders, and is overall fatal.

Cost savings will be in proportion to the rate of mis-triage in the pre-hospital setting. Current prehospital assessment tools (LAS and HITS-NS triage tools) demonstrate poor sensitivities of 44.5% (95% CI 43.2–45.9) and 32.6% for TBI, resulting in a considerable proportion of significant head injury patients not following national guidance to be triaged directly to trauma centers. Extensive literature showing that even marginal refinements in triage tools can lead to substantial cost-savings from reduced direct healthcare costs and Disability-Adjusted-Life-Years, although figures vary significantly depending on local care provision and tariffs.

We do not envisage that the device would obviate the need for a CT scan in patients meeting nationally agreed criteria (e.g., NICE in the UK), at least not in well-resourced healthcare systems. However, it would enable more timely management of an occult TBI pre-hospital, including early-neuroprotective measures and correct triage to the most appropriate facility with or without neuroscience expertise.

The system could replace the need for an unnecessary initial or follow-up CT scan in some cases, which, in many instances, can lead to families needing to sell personal assets to pay for the procedure.

Beyond the lab-based bench-top prototyping, further enhanced by the scaled-up manufacturing, the added value of the portable device, the socioeconomic cost of TBI and the final anticipated cost per test, there are no foreseen barriers to widespread deployment of the developed technology, which would be a cost-effective, portable, and easy-to-use medical device that could be incorporated into pre-hospital and hospital equipment lists and capability.

Q: Why does Raman spectroscopy offer a good solution?

A: Our device will allow early TBI diagnosis by directly assessing acute distress changes in real time in living neuro-retinal/optic nerve tissue. It enables direct and non-invasive interrogation of the central nervous system (CNS). The use of Raman spectroscopy to read optical signals from the retina/optic nerve means that assessment is non-contact and results are effectively instant. There are no directly comparabletechnologies currently in use.

The main advantage of measuring changes in optical biomarkers in comparison to other techniques is that this can be done quickly and noninvasively. Additionally, a Raman spectrometer made compact and using minimal energy requirements brings a non-invasive method to probe the posterior segment of the eye to detect TBI at the point-of-care and monitor injury evolution in real time.

Among the optical techniques, Raman offers the richest and most sensitive spectroscopic discrimination, whereas a Raman spectrum defines a chemical fingerprint that is uniquely determined by the underlying molecular constituents.

Raman spectroscopy with fundus imaging to assess the retina/optic nerve is non-contact and provides effectively instant results. Raman is one of the most sensitive and information-rich spectroscopic methods for biochemical discrimination providing unique molecular fingerprints.

In comparison to other techniques, optical biochemical changes can be done quickly and noninvasively. Additionally, a Raman spectrometer-made compact and minimal energy requirements enables a non-invasive method to probe the posterior segment of the eye to detect TBI at the point-of-care and monitor injury evolution in real-time.

The above provides a low-cost, hand-held device to analyze the neuroretina, as a window into brain biochemistry. Thus, it could provide the first tangible path towards non-invasive, rapid diagnostics of TBI at the point-of-care.

Q: Is this system being used on patients currently? Is there a plan for that in the future?

A: We are currently optimizing the prototype for clinical validation of Raman-fundus spectroscopy, engineering user-friendly deployable device, integrated with our artificial neural network algorithm for an automated interpretation of outputs without requiring specialist support, rapidly classifying spectral data, and clinically evaluating device usability in healthy volunteers and in patients to demonstrate its potential for real-time diagnosis.

After establishing device tolerability and usability, we are proceeding to a first-in-human evaluation and small-scale clinical trial.

Q: What research still needs to be done in this space?

A: Firstly, we developed a bespoke artificial neural network algorithm SKiNET (self-optimizing Kohonen index network) as a generic framework for multivariate analysis that simultaneously provides dimensionality reduction, feature extraction, and multiclass classification as part of a seamless interface. Using SkiNET, we classified TBI from spectral data and established validation on mouse eyes by detecting and classifying tissue-specific signatures of each anatomical layer on eye-sections. SKiNET-software integrated in final device will act as a decision support tool, where interpretation of Raman data will be automated and will not require specialist support, dramatically improving the speed and cost of diagnosis.

In ex vivo murine retina, we have demonstrated feasibility of Raman in differentiating TBI from healthy controls with a high degree of accuracy across a range of injury severities. This agreed with measurements from brain data, which separates according to injury state and observed spectral changes associated with cardiolipin and metabolic distress.

Further experiments performed on pig eyes using 633nm excitation wavelength detected molecular fingerprints of TBI neuromarkers and subsequently, from eye sections, we observed an apparent enhancement of high wavenumber bands and data display a clear separation between control and TBI groups using SKiNET.

We have further developed a portable proof-of-concept Raman-fundus device able to measure signals in short timescales. This device measures Raman spectra from the optic nerve using an incident collimated beam, focused by the cornea onto the retina (CE marked Class I laser). We reached the point where extensive animal studies on TBI identification with both laboratory-based and portable Raman are laying the groundwork towards the development of in vivo clinical measurements using a new portable eye-safe device.

We are currently optimizing the prototype for clinical validation of Raman-fundus spectroscopy, engineering user-friendly deployable device, integrated with our artificial neural network algorithm for an automated interpretation of outputs without requiring specialist support, rapidly classifying spectral data, and clinically evaluating device usability in healthy volunteers and in patients to demonstrate its potential for real-time diagnosis.

After establishing device tolerability and usability, we are proceeding to a first-in-human evaluation and small-scale clinical trial.

Q: Anything that surprised you about this research that our readers should know?

A: It has been a long journey so far with ups and downs to get the integrated system to work, with surprises along the way, as well a true excitement of getting a signal from the brain through the eye.

References

(1) Banbury, C.; Harris, G.; Clancy, M., et al. Window into the mind: Advanced handheld spectroscopic eye-safe technology for point-of-care neurodiagnostic. Sci. Adv. 2023, 9 (46). DOI: https://doi.org/10.1126/sciadv.adg5431

(2) Traumatic Brain Injury & Concussion: Get the Facts. Centerns for Disease Control and Prevention 2021. https://www.cdc.gov/traumaticbraininjury/get_the_facts.html (accessed 2023-1-9)

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